Process for crystallizing L-α-aspartyl-L-phenylanlanine methyl ester

ABSTRACT

A crystalline L-alpha-aspartyl-L-phenyl-alanine methyl ester product is disclosed. The product is obtained by crystallizing the ester from an aqueous solution, by cooling. The initial concentration of ester in the aqueous solution used provides at least 10 grams of precipitated solid phase per liter of solution. The solution is cooled through conductive heat transfer without effecting forced flow to form a sherbet-like pseudo solid phase.

This is a Continuation of application Ser. No. 08/655,945, filed on May31, 1996, pending, which is a Continuation of Ser. No. 08/462,551, filedon Jun. 5, 1995, now U.S. Pat. No. 5,621,137; which is a Continuation ofSer. No. 08/173,946, filed on Dec. 28, 1993, abandoned, which is aContinuation of application Ser. No. 07/879,120, filed on May 5, 1992,abandoned, which is a Continuation of Ser. No. 07/475,403, filed on Feb.5, 1990, abandoned, which is a Continuation of Ser. No. 07/293,565,filed on Jan. 3, 1989, now U.S. Pat. No. 5,041,607, which is aContinuation of 07/054,494, filed on May 27, 1987, abandoned, which is aContinuation of Ser. No. 06/839,819, filed on Mar. 12, 1986, abandoned,which is a Continuation of Ser. No. 06/482,542, filed on Apr. 6, 1983,abandoned.

DETAILED DESCRIPTION OF THE INVENTION:

This invention relates to a process for crystallizing and separatingL-α-aspartyl-L-phenylalanine metyl ester under some specificcrystallization conditions.

L-α-aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated asAPM) is a substance which is expected to find wide applications as a newlow-calorie sweetener due to its good sweetening properties. Asprocesses for industrially producing this APM, the following processesare typical.

That is, there are known a process of binding an N-substituted asparticacid anhydride with phenylalanine methyl ester in an organic solvent(U.S. Pat. No. 3,786,039), a process of directly binding a.,strong acidaddition salt of aspartic acid anhydride with phenylalanine methyl ester(Japanese Patent Publication No. 14217/74), a process of condensing anN-substituted aspartic acid with phenylalanine methyl ester in thepresence of an enzyme and eliminating the substituent (Japanese PatentPublication No. 135595/80), and the like.

In industrial production, crystallizing step of isolating APM from areaction solution is necessary for obtaining a final product in any ofthe processes described above. This crystallizing step is usuallyconducted, for example, by re-dissolving a crude product in water,organic solvent or aqueous organic solvent, cooling the solution throughheat exchange with a refrigeration medium (forced cyclization typeindirect cooling system) or evaporating part of the solvent underreduced pressure (self-evaporating system) using a crystallizer equippedwith a stirring means, and dewatering and filtering out the thusprecipitated crystals by means of a centrifugal separator or the like.

However, the thus obtained APM crystals have fine needle-like crystalhabit, and therefore show extremely bad solid-liquid separability infiltration and dewatering procedure thus the above-described processesinvolving practical problems.

To illustrate one case, when 600 liters of a slurry containing APMcrystals obtained by one of the above-described processes (seeComparative Example) was subjected to solid-liquid separation byfiltering for 2 hours and dehydrating for one hour in a centrifugalseparator having a diameter of 36 inches and a volume of 92 liters(number of revolutions: 1,100 r.p.m.; centrifuging effect: 600 G), theresulting cake had a water content of 45 to 50% or more. The watercontent as used herein is defined as (water amount in the cake/wholeamount of wet cake)×100%.

In addition, there is found another defect that, when a series of theprocedures of scraping this cake and conducting solid-liquid separationof a fresh slurry containing APM crystals are repeated, the base layerof cake becomes so tightly hardened that its removal requires much laborand time.

Further, in a drying step following the crystallizing step, drying loadis too high due to its high water content of the cake, and the resultingpowder has such large bulk specific volume that it is extremelydifficult to handle.

Table 1 shows powder properties of APM crystals obtained by thecrystallizing process of the present invention (see Example 1) and thatobtained by one conventional process (see Comparative Example).

                  TABLE 1    ______________________________________                    Conventional                            Process of                    Process the Invention    ______________________________________    Static specific volume (cc/g)                      6-7       3-4    Close specific volume (cc/g)                      3-4       2-3    Rate of dissolution (min.)                      14-17     5-6    ______________________________________

In crystallizing other materials, it has been known that theabove-described problems in the crystallizing procedure can be removedby conducting tthe crystallization employing a low concentration and aslow cooling rate to obtain crystals having a large diameter. With APMcrystals, however, such crystallization procedure results in formationof needle-like crystals growing only in a longitudinal direction,failing to provide expected effects. For example, when seed crystalswere added to a 0.8 wt % APM solution and the solution temperature wasdecreased from 15° C. to 5° C. in two days, crystals grew 214% in thelength direction but only 15% in the diameter direction.

As a result of intensive investigations to improve workability of theaforesaid step in the production of APM by examining various conditions,the inventors have found the following novel facts.

That is, surprisingly, it has been found that, in crystallizing APM fromits solution of a certain concentration or above by cooling withoutstirring, APM crystals take up the solvent into the space formed amongthem, and the whole solution thus appears apparently solidified, andthat the crystals obtained in this state show extremely good propertiesin subsequent solid-liquid separation procedure. Observation of thecrystals under a scanning type electromicroscope revealed that severalneedle-like crystals are bundled to form an apparently one crystal (tobe described hereinafter).

The bundle-like crystal aggregate of the present invention are extremelystrong against physical impact as long as they are not under growing ina supersaturated solution, and have been confirmed to maintain 5- to10-fold or more diameter as compared to that of conventional crystalseven after being transported, separated or dried.

More surprisingly, even under such crystallizing condition that, withordinary substances, crystals fixedly deposit on a heat-transferringsurface to cause so-called scaling which is difficultly removable,precipitation of APM crystals in accordance with the present inventionis found to enable to completely remove the crystal layer from thecooling surface.

As a result of intensive investigations to apply the above-describedfindings to an actual process, the inventors have achieved remarkableimprovement in workability in the step of precipitating APM crystalsfrom an APM solution by cooling the solution under the condition offorming a pseudo solid phase to obtain crystals showing goodseparability, thus having completed a novel crystallizing processproviding industrially great economical effects. As a result of furtherinvestigations, the inventors have found that, once the solution takes apseudo solid phase, it can maintain its good separability even whensubjected to a desupersaturation procedure of rapid cooling accompaniedby causing forced flow, which serves to increase the efficiency of thestep and improve crystallization yield, thus having completed thepresent invention.

That is, a characteristic aspect of the present invention is to obtainbundled, large-diameter APM crystal aggregates by cooling as fast aspossible an APM aqueous solution employing such crystallizing conditionsor crystallizers that natural heat transfer by convection is realizedonly in the very early stage of the crystallizing step, then heattransfer is controlled by conduction. According to the presentinvention, solid-liquid separability and powder properties of theproduct can be improved, workability in each step being remarkablyimproved. Therefore, the present invention provides an APM-crystallizingprocess which is economically quite advantageous. Additionally, due tothe above-described properties of the present invention, APM crystalshaving bad crystal habit can be converted to APM crystals having goodcrystal habit by the recrystallization process in accordance with thepresent invention, and APM, containing impurities such asdiketopiperazine (DKP), an cyclized product of APM, andL-α-aspartyl-L-phenylalanine can be freed of the impurities bysubjecting the impurities-containing APM to the crystallizing process ofthe present invention coupled with a decrease in the amount of adheringmother liquor in solid-liquid separation and improvement in cakewashability.

The present invention will now be described in more detail below.

In the process of the present invention, cooling is conducted withoutforced flow caused, for example, by mechanical stirring. Additionally,it is desirable to render the whole solution into a sherbet-like pseudosolid phase to finish natural flow phenomenon resulting from temperaturedistribution as fast as possible. For the purpose of comparison,electronmicroscopic/photographs of bundled crystals obtained by theprocess of the present invention (FIG. 1A (x58), and FIG. 1B (x580)),fine crystals obtained by indirect cooling under forced flow, one of theconventional processes (FIG. 2A (x560) and FIG. 2B (x11280)), anddendrite crystals obtained without causing forced flow and under suchcondition that no sherbet-is formed (FIG. 3A (x51) and FIG. 3B (x350)).From these photographs, it can be easily understood that the threecrystals, which show the same results in X-ray powder diffractiometry,are clearly different from each other in shape and size due to thedifference in crystallizing manner.

Type IB of the bundle-like and the needle-like crystals on a laboratoryscale

In order to obtain the bundle-like and the needle-like crystals withdifferent crystal sizes, 13 sample crystals were prepared under theseveral crystallizing conditions summarized in Table 1 as follows:

Some amount (X g) of aspartame was dissolved in 1500 g of ion-exchangedwater and stirred at 70° C. for 1 h. This solution was crystallized atthe cooling rate (Y K/h) to 5° C. with stirring (Z rpm) or withoutstirring, and the supersaturation was released with stirring overnight.After the slurry was filtered, the wet crystals were dried in a vacuumoven at 40° C. overnight.

The type IB of the bundle-like crystals on a bench plant scale

The type IB of the bundle-like crystals were prepared using an apparatusshown in FIG. 9 of the above-identified application.

Aspartame solution was charged in a stainless steel-made crystallizerhaving a diameter of 400 mm (maximum distance between the cooledsolution and the cooling surface: 75 mm) and having jacket 3 and innercooling plates 2, and a 0° C. refrigeration medium was circulatedthrough the jacket and the cooling plates to conduct cooling for 3hours, during which cooling through heat transfer by conduction becamepredominant about 15 minutes after initiation of the cooling. The wholesolution became a pseudo solid phase after about one hour.

Thereafter, the contents were discharged into tank 7 equipped withcooling coil 5 and stirrer 6 to destroy the solid phase.

When the thus obtained slurry was filtered and dewatered using acentrifugal separator 8 having a diameter of 36 inches, then dried at40° C. and dry crystal (sample 14) was obtained.

The type IB of the needle-like crystals on a bench plant scale

Needle-like crystals were prepared using an apparatus shown in FIG. 10of the above-identified application.

A feed solution was continuously introduced through feed inlet 8. Twostainless steel tanks 4 (volume: 100 liters) equipped with--stirrer 1,outer heat-exchanger 2, and jacket 3 were used in series. Stirring speedwas 50 rpm. APM concentration of the feed solution was 4.4 wt %, and theflow rate was 60 liters/hr. The average temperature in the first tankwas 25° C. and that in the second tank 10° C. Additionally, in FIG. 10,numeral 5 designates a receiving tank equipped with stirrer 1 andcooling coil 6, and 7 designates a centrifugal separator, then dried at40° C. and dry crystals (Sample 15) was obtained.

Quasi-amorphous of the needle-like crystals

Completely amorphous aspartame can not be prepared, so quasi-amorphousaspartame was use instead. Quasi-amorphous aspartame was prepared asfollows: 67.5 g of aspartame was dissolved in 1500 g of ion-exchangedwater and stirred at 70° C. for 1 h. This solution was cooled at therate of 10° C./h to 5° C. at a stirring rate of 300 rpm. Thesupersaturation was released overnight. The resulting precipitate wasfiltered and dried in a vacuum oven at 40° C. overnight. Its powder XRDpattern shows an amorphous halo with only one peak at lower than 5° in2θ angle.

Characterization of crystal texture

X-ray diffraction analysis--The powder XRD patterns were obtained withan X-ray diffractometer (Phillips PW1700) and in the 2θ ranges of3°≦2θ≦30° using CuK α radiation. The voltage was 40 kV, and the currentwas 30 mA.

Determination of the relative degree of the crystallinity--A perfectcrystalline aspartame does not exist so it is impossible to determinethe absolute degree of crystallinity of an aspartame crystal. Acomparative basis for the characterization of the crystallinity wastherefore investigated. A series of crystal mixtures of the crystalsample 1 (the bundle-like crystal) and the quasi-amorphous were preparedin appropriate wt.%. In general, the amount of the crystalline part hasbeen considered to be measured by the total integrated intensity abovethe background line. The scatter beneath the background line consists ofcoherent amorphous scatter, incoherent and thermal scatter. However, itis impossible to draw exactly a background line in a powder XRD patternof aspartame because it is produced with many superimposed peaks. Thewhole length of the diffraction lines which was quantified by all thenumber of dots was examined as an index of the crystallinity. The powderXRD patterns were recorded on a 408×408 dots array covering the 2θ rangefrom 5° to 30° in the horizontal axis and the intensity range from 0 to100 kcps in the vertical axis. The crystallinity index (Cr. Index) isdefined as follows:

    Cr. Index=WLDL/TTR

where WLDL is the number of dots of whole length of diffraction line andTTR is the number of dots of the 2 θ range which is here fixed to 408dots. There is a good correlation between the weight fractions ofaspartame crystals and the values of the normalized whole length ofdiffraction lines. It is suggested that the normalized whole length ofthe diffraction lines is an effective index to indicate thecrystallinity of aspartame crystals. The Crystallinity Index is an indexof the degree of crystallinity of aspartame crystals.

Determination of the degree of the preferred orientation--The preferredorientation is observed as the difference between an experimental and atheoretical powder XRD pattern. The degree of preferred orientation ischaracterized by the comparison of the measured intensity with thetheoretical one of a selected peak which is sensitive to preferredorientation in powder XRD pattern. The theoretical powder XRD patternsimulated from the crystal structure with an application software(Cerius. Molecular Simulations Inc.) is shown in FIG. 3. The structureof type IB crystal with three aspartame molecules and two watermolecules per asymmetric unit, has been refined to an R factor of about14%. The intensity of the (113) reflection is found to be strongest inthe 2θ ranges of 3°≦2θ≦30° of the theoretical pattern. In the measuredXRD patterns of the bundle-like crystals the intensity of the (hOl)reflections, especially (301), are relatively stronger than thetheoretical intensity. The preferred orientation index (P.O. Index) isdefined by the ratio of the intensity of the (301) reflection to theintensity of the (113) reflection, ##EQU1##

The suffix m denotes a measured value, and s denotes a theoreticalvalue. The P.O. Index is normalized by the theoretical value and isequal to 1 when there is no preferred orientation.

A comparison of the powder XRD patterns of sample I (bundle-likecrystal) and sample 10 (needle-like crystal) show that they have thesame crystal form, but their diffraction profiles are different. In thecase of sample 1 the diffraction intensities of (hOl), i.e. (301)(2θ=12.0°), (204) (2θ=15.1°) and (400) (2θ=18.5), are relativelystronger, while in the case of sample 10 the diffraction profile issimilar to the standard pattern (FIG. 3) although their peaks are lowand broad. The anomalous diffraction pattern of sample 1 indicates highcrystallinity and high preferred orientation with respect to thedirection along to the b-axis. This preferred orientation of sample 1 isdue to its internal structure, that is, anisotropic disorder, since itsremoval through grinding can not be achieved. The characteristicproperties of the crystal texture evaluated from these diffractionpatterns are as follows: The Crystallinity Indices of sample 1 and 10are 8.0 and 3.9, respectively. P.O. indices of sample 1 and 10 are 2.9and 1.3, respectively.

In the bundle-like crystals such as sample 1, the parallel regularity ofthe direction of the b-axis is higher than the other direction, in otherwords, the degree of disorder along the b-axis is larger than the a- andc-axes. In the needle-like crystal (sample 10), the degree of disorderin any direction is larger than that in the bundle-like crystal(sample 1) and about of the same order of magnitude as each other, andthere may be frequent large lattice distortions.

In the case of a bench plant scale, the Crystallinity Indices of sample14 and 15 are 7.0 and 3.4 respectively. P.O. Indices of sample 14 and 15are 4.2 and 1.3 respectively.

                                      TABLE 1    __________________________________________________________________________    Crystallizing conditions and crystal texture of the samples    Sample No.          1  2  3  4  5  6  7  8  9  10 11 12 13    __________________________________________________________________________    Weight          67.5             67.5                45.0                   45.0                      37.5                         37.5                            67.5                               67.5                                  45.0                                     45.0                                        37.5                                           37.5                                              45.0    Crystals X     g!    Cooling          385             15 385                   15 385                         15 385                               15 385                                     15 385                                           15 15    Rate Y     K/hr!    Stirring Rate          0  0  0  0  0  0  300                               300                                  300                                     300                                        300                                           300                                              300    Z  rpm!    Granulation          -- -- -- -- -- -- -- -- -- -- -- -- ∘    Crystallinity          8.0             8.1                6.6                   7.3                      6.2                         7.5                            3.8                               4.3                                  3.6                                     3.9                                        4.2                                           3.9                                              2.3    Index    P.O. Index          2.9             2.7                2.2                   2.3                      2.4                         2.4                            1.5                               1.7                                  1.3                                     1.3                                        1.0                                           1.4                                              1.0    __________________________________________________________________________

As a crystallizer for satisfying the above-described procedureconditions, FIG. 4 shows an example of continuous crystallizers, inwhich a jacketed U-tube having nozzles on both ends is used. Uponinitiation of the crystallizing procedure, a feed solution is previouslycharged in the tube before initiation of cooling. At a stage wherecrystallization has proceeded in the tube, feed solution is pressed intothe tube through feed inlet 1 at a slow rate, upon which a sherbet-likeslurry is pressed out of the tube through opposite outlet 2. Thesherbet-like slurry can be continuously obtained onward by coolingthrough heat transfer by conduction and feeding the solution in suchflow rate that enough residence time for crystallization to be completedis attained.

Additionally, the crystallizer may not necessarily be a U-tube, and avertical or horizontal straight tube and any curved tube that does notsuffer pressure loss more than is necessary may be employed as well.

FIG. 5 shows an example of batchwise crystallizers. Feed solution isintroduced through feed inlet 1. After completion of charging thesolution, a refrigeration medium is introduced into cooling plates 2 orcooling tube and jacket 3 to cool the contents. After a predeterminedperiod of time, discharge valve 4 is opened to discharge a sherbet-likeslurry.

FIGS. 6 and 7 show examples of conducting the process of the presentinvention using a conventional apparatus. Procedures are continuous inboth cases.

In FIG. 6, a rotating steel belt is used as a cooling surface (the beltbeing cooled, for example, by blowing a refrigeration medium to the backof the belt), and a feed solution is continuously introduced onto thebelt to crystallize. The formed sherbet-like slurry is recovered byscraping with scraper 1 provided on the other end. In this embodiment,for the purpose of forming a thick sherbet layer on the belt, guides 2may be provided on the sides of the belt, or a frame may be fixedlyprovided on the belt to thereby prevent the solution from flowing overbefore solidifying. In some cases, semi-continuous procedure may beemployed.

FIG. 7 shows an embodiment of utilizing an evaporate-condenser. A feedsolution is introduced to the center 3 of two contact-rotating drums 1rotating outward. The drums are cooled from inside with a refrigerationmedium instead of being heated from inside with steam, on which sherbetdeposits as a result of crystallization. The thus formed sherbet isscraped by scrater 2.

These embodiments are particularly designed or intended for satisfyingthe aforesaid special conditions of the crystallization to-be employedin the process of the present invention. The inventors do not know thatthe above-described apparatuses have been used for crystallizing APM aswell as other materials through heat transfer by conduction. Processesfor crystallizing APM with the use of any other apparatuses whichsatisfy the specific crystallization conditions of this invention are ofcourse within the scope of this invention.

To attain an apparantly solidified state, the solution must containabout 10 g or more solids per liter of the solvent at the point. Thatis, in an aqueous solution system, satisfactory recovery of APM can beattained by cooling the system to 5° C., taking the solubility of APMinto consideration. Theoretically, an initial concentration of the APMsolution before crystallization of 1.5 wt % suffices since thesaturation concentration at the temperature is 0.5%. However, in a lowsupersaturated region, crystallizing rate is too slow. Therefore,practically the aqueous system must contain about 2 wt % or more APM forforming the sherbet state. In order to obtain crystals having largediameter, solidification must proceed at faster rate. For this purpose,the initial concentration is desirably about 3 wt % or more.

FIG. 8 shows the results of measuring solubility of APM in water.

On the other hand, the upper limit of the concentration depends uponstability of APM in solution at elevated temperatures and its solubleconcentration and, in the aqueous system, a concentration of about 10%or less, which is a saturation concentration of APM at 80° C., is ausually suitable upper limit.

As the crystallizing solvent, water suffices, which may optionallycontain other solvents as long as the spirit of the present invention isnot spoiled, i.e., no particular troubles take place in the practice ofthe present invention.

For effectively practicing the process of the present invention, coolingrate is an important procedure factor. However, in the cooling stepbased on heat transfer by conduction, a temperature distribution appearswithin a solution being cooled, and the cooling rate is not timewiseconstant, thus definite control of cooling rate being difficult.However, an average temperature of cooled solution after a given periodof time is decided by the temperature of a refrigeration medium used,initial temperature of the cooled solution, and maximum distance betweencooled solution and the heat-transfer surface. The initial temperatureof cooled solution depends upon the aforesaid concentration of APM and,as the refrigeration medium, a known one such as propylene glycol,ethylene glycol or cooling water may be used. The temperature of therefrigeration medium is most suitably -5° C. to 35° C. in view ofprevention of freezing of the solvent and time required for cooling.Further, as to the maximum distance between the cooled solution andheat-transfer surface, the larger the distance, the more the differencein crystallization degree due to greater temperature distribution withinthe cooled solution. In addition, decomposition of APM proceeds so muchthat predetermined supersaturation cannot he attained, thus separabilitybeing adversely affected much. Therefore, even the remotest part of thesolution being cooled is desirably 500 mm or less from the heat-transfersurface. In any case, those skilled in the art can easily findconditions necessary for rendering the whole solution into a pseudosolid phase in the illustrated crystallizers, which are the marrow ofthe present invention, through simple preliminary experiments.

The thus obtained sherbet-like pseudo solid phase comprising APMcrystals and the solvent dose not itself show any fluidity, but showsextremely good separating properties from the cooling surface, thuscausing no troubles upon discharge out of the crystallizer. It can beeasily destroyed into a slurry, for example, by stirring and can hetransported through pumps or the like.

Additionally, in the process of the present invention, cooling of thesystem is conducted through heat transfer by conduction, and hence itrequires a longer time to cool to a desired temperature than that incooling under forced flow. Needless to say, the process of the presentinvention provides more advantages than compensate for the disadvantage.However, in order to more raise efficiency and improve yield, it ispossible to conduct desupersaturating procedure subsequent to theaforesaid crystallizing step.

That is, the sherbet-like pseudo solid phase obtained by crystallizationthrough heat transfer by conduction and comprising APM crystals and thesolvent is rapidly cooled subsequent to destruction of the solid phase,for example, by stirring to thereby remove residual supersaturation in ashort time. However, where the proportion of APM crystalsadditionally-precipitated in the desupersaturating procedure accountsfor about 25% or more of the whole solid phase APM finally obtained,solid-liquid separability of the slurry is sharply deteriorated.Therefore, the desupersaturation to be carried out is desirablycontrolled to less than the above-described degree.

The present invention will now be described in more detail by thefollowing non-limiting examples of preferred embodiments of the presentinvention.

EXAMPLE 1

This example was conducted using an apparatus shown in FIG. 9.

380 Liters of a feed solution containing dissolved therein 17.7 Kg ofAPM (containing 3% DKP)(55° C.; initial concentration of APM: 4.4 wt %)was charged in a stainless steel-made crystallizer having a diameter of400 mm (maximum distance between the cooled solution and the coolingsurface: 75 mm) and having jacket 3 and inner cooling plates 2, and a 0°C. refrigeration medium was circulated through the jacket and thecooling paltes to conduct cooling for 3 hours, during which coolingthrough heat transfer by conduction became predominant about 15 minutesafter initiation of the cooling. The whole solution became a pseudosolid phase after about one hour.

Thereafter, the contents were discharged into tank 7 equipped withcooling coil 5 and stirrer 6 to destroy the solid phase. In thisoccasion, the average temperature of the slurry was about 16° C., andthe APM concentration of the mother liquor was 0.9 wt %. Then, arefrigeration medium was introduced into the coil under further stirringto conduct cooling for one hour to thereby lower the temperature of theslurry to about 7° C. The APM concentration of the mother liquor was 0.7wt %.

When the thus obtained slurry was filtered and dewatered a centrifugalseparator 8 having a diameter of 36 inches, water content of the cakedecreased to 25% only after 20 minutes. Yield: 19 Kg (wet); recoveryratio: 86%; DKP content: 0.1%.

Additionally, APM crystals additionally precipitated in thedesupersaturation procedure accounted for about 5% of the whole solidphase finally obtained.

Similar results were obtained by crystallizing APM using an apparatushaving cooling tube in place of the cooling plate.

With a slurry obtained by a conventional process (see ComparativeExample to be described below), the water content was as high as 45 to50% even after 2-hour filtration and 1-hour dewatering (3 hoursaltogether).

COMPARATIVE EXAMPLE

This comparative example was conducted using an apparatus shown in FIG.10. A feed solution was continuously introduced through feed inlet 8.Two stainless steel tanks 4 (volume: 100 liters) equipped with stirrer1, outer heat-exchanger 2, and jacket 3 were used in series. Stirringspeed was 50 r.p.m.. APM concentration of the feed solution was 4.4 wt%, and the flow rate was 60 liters/hr. The average temperature it thefirst tank was 25° C. and that in the second tank 10° C. Additionally,in FIG. 10, numeral 5 designates a receiving tank equipped with stirrer1 and cooling coil 6, and 7 designates a centrifugal separator.

Results of comparing the process of the present invention with theconventional process with respect to centrifuge-filtration rate andcentrifuge dewatering rate are shown in FIG. 11A and FIG. 11B,respectively. -- shows the measured values with APM slurry inaccordance with the present invention, and ◯--◯ shows the measuredvalues with APM slurry obtained by the conventional process.

In leaf test by suction filtration to determine specific resistancevalue, the APM slurry obtained by the process of the present inventionshowed a specific resistance of 1×10⁶ to 2×10⁸ m/Kg immediately afterbeing discharged and 3×10⁸ to 5×10⁸ m/Kg after desupersaturation,whereas the slurry obtained by the conventional process showed aspecific resistance of 5×10¹⁰ to 1×10¹¹ m/Kg.

EXAMPLE 2

A feed solution having the same composition as in Example 1 was cooledusing a steel belt cooler (1.2 m×5 m; made by stainless steel) as shownin FIG. 12 to crystallize APM. The feed solution was continuouslyintroduced onto the belt through feed inlet 3. Where feed amount islarge, it is preferable to provide guides 2 on the sides of the belt forpreventing overflow. In such cases, the guides are not necessarilyprovided over the full length of the belt, because the solution does notflow out after being rendered sherbet-like.

Cooling was conducted indirectly by jetting 12° C. cooling water to theback of the belt. The solution-feeding rate and the belt speed wereadjusted so that the thickness of sherbet, or maximum distance from thecooling surface, became about 10 mm.

The thus obtained sherbet containing APM crystals and water was scrapedout by scraper 1 and destroyed in receiving tank 4 by stirring (60r.p,m.) into a slurry. The average temperature of the productimmediately after scraping was about 18° C. Additionally, cooling fordesupersaturation was not particularly conducted in the receiving tank.

When about 100 liters of the slurry in the receiving tank was subjectedto solid-liquid separation in centrifugal separator 5, the water contentof cake was reduced to about 30% after 30 minutes. Yield: 4.3 Kg. Theseparated mother liquor contained about 1.5 wt % APM. recovery ratio:68%.

This steel-belt cooler system has the advantages taht, as compared tothe system of Example 1, cooling surface can be smaller due to largerprocessing speed and that, in view of process flow, a feed solution isnot necessarily kept at high temperature because of continuous system,thus decomposition of APM being remarkably reduced.

As is clear from the above descriptions and examples, application of theprocess of the present invention to crystallization and separation ofAPM crystals provides the following outstanding advantages in view ofindustrial point of view as compared to conventional processes, forexample, of forced circulation-outer cooling system or self evaporationsystem, though energy load required for cooling, etc. is almost thesame.

(1) As to solid-liquid separation of a slurry containing APM crystals, aslurry obtained by the conventional process is difficult to reduce itswater content to the degree attained by a slurry obtained by the processof the present invention even when separation time is prolonged.

(2) In repeatedly conducting the above-described separation procedure, aslurry obtained by the conventional process suffers tightpress-solidification of cake base layer, its removal requiring muchlabor, whereas a slurry obtained by the process of the present inventiondoes not undergo such phenomenon. For example, in one embodiment of theprocess of the present invention, the base layer could be easily removedfrom the filter surface even after 20 times repeating the procedure,whereas repeated procedure according to the conventional processresulted in tight solidification only after 5 times repeating theprocedure, the thus solidified base layer being difficultly removable.

(3) To evaluate the shortening of filtration time and reduction ofseparation load such as cake removal, realized by applying the processof the present invention, in terms of required filter area, the processof the present invention reduced the area to about 1/10 or less of thearea of the conventional process.

(4) Additionally, the remarkable improvement of separability isaccompanied by reduction of adhesion of impurity-containing motherliquor onto the crystals to 1/2 and improvement of washing effect, andhence crude crystallization step may be eliminated by combining cakewashing procedure or the like.

(5) Load in a drying step is decreased to about 1/3. For example, dryingload necessary for obtaining 100 Kg of dry product powder (watercontent: 3%) is as follows. With APM crystals containing 50% water andobtained by the conventional process, the load is 5.1×10⁴ Kcal, withneglecting loss in heat transfer procedure, whereas with APM crystalscontaining 25% water and obtained by the process of the presentinvention, it is 1.6×10⁴ Kcal.

(6) Dry powder properties are so remarkably improved as shown in Table 1that handling properties of the powder are improved.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A and FIG. 1B are electronmicroscopic photographs of APM crystalsobtained by the process of the present invention.

FIG. 2A and FIG. 2B are electronimicrographs of APM crystals obtained bythe conventional process.

FIG. 3A and FIG. 3B are electron microscope photographs of APM crystalsobtained without causing forced flow and under such condition that nosherbet is formed.

FIGS. 4, 5, 6, and 7 show examples of crystallizers to be used in thepresent invention.

FIG. 8 shows solubility of APM in water.

FIG. 9 shows a crystallizer used in Example 1.

FIG. 10 shows a crystallizer used in conventional process.

FIG. 11A and FIG. 11B show the results of comparing the process of thepresent invention with a conventional process with respect to filtrationrate and dehydration rate of APM slurry.

FIG. 12 shows a crystallizer used in Example 2.

What is claimed is:
 1. A bundle-type crystal ofL-α-aspartyl-L-phenylalanine ethyl ester having diffraction lines2θ=12.0°, 15.1°, 18.5° and 21.5° and a P.O. index of from 2.2to 4.2. 2.The bundle-type crystal of claim 1, wherein said P.O. index is from 2.2to 2.9.
 3. The bundle-type crystal of claim 1, wherein said crystal hasa crytallinity index of from 6.2 to 8.1.